Deficient degradation of homotrimeric type I collagen, I+/-1(I) sub(3) glomerulopathy in oim mice
Col1a2-deficient (oim) mice synthesize homotrimeric type I collagen due to nonfunctional proI+/-2(I) collagen chains. Our previous studies revealed a postnatal, progressive type I collagen glomerulopathy in this mouse model, but the mechanism of the sclerotic collagen accumulation within the renal m...
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Published in | Molecular genetics and metabolism Vol. 104; no. 3; pp. 373 - 382 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
01.11.2011
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Online Access | Get full text |
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Summary: | Col1a2-deficient (oim) mice synthesize homotrimeric type I collagen due to nonfunctional proI+/-2(I) collagen chains. Our previous studies revealed a postnatal, progressive type I collagen glomerulopathy in this mouse model, but the mechanism of the sclerotic collagen accumulation within the renal mesangium remains unclear. The recent demonstration of the resistance of homotrimeric type I collagen to cleavage by matrix metalloproteinases (MMPs), led us to investigate the role of MMP-resistance in the glomerulosclerosis of Col1a2-deficient mice. We measured the pre- and post-translational expression of type I collagen and MMPs in glomeruli from heterozygous and homozygous animals. Both the heterotrimeric and homotrimeric isotypes of type I collagen were equally present in whole kidneys of heterozygous mice by immunohistochemistry and biochemical analysis, but the sclerotic glomerular collagen was at least 95-98% homotrimeric, suggesting homotrimeric type I collagen is the pathogenic isotype of type I collagen in glomerular disease. Although steady-state MMP and Col1a1 mRNA levels increased with the disease progression, we found these changes to be a secondary response to the deficient clearance of MMP-resistant homotrimers. Increased renal MMP expression was not sufficient to prevent homotrimeric type I collagen accumulation. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 content type line 23 ObjectType-Feature-1 |
ISSN: | 1096-7192 |
DOI: | 10.1016/j.ymgme.2011.07.025 |